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    • 专利摘要:
    The invention relates to novel oxime ethers of the general formula /I/ and acid addition salts and quaternary ammonium derivatives thereof, <IMAGE> /I/ wherein A represents a C2-6 straight or branched alkylene chain, R and R1 each represent a C1-6 alkyl group or they form together with the adjacent nitrogen atom a heterocyclic ring containing 4 to 7 carbon atoms and optionally a further hetero atom, i.e. an oxygen, sulfur or nitrogen atom, and said ring may be optionally substituted by a C1-3 alkyl, phenyl or benzyl group, R2 and R3 each denote a hydrogen atom or together form a valency bond, R4 denotes a C1-10 alkyl or C2-10 alkenyl group, and n denotes an integer from 3 to 7. The compounds of the general formula /I/ are prepared according to the invention by reacting a cycloalkane derivative of the general formula /II/ <IMAGE> /II/ wherein R2, R3, R4 and n have the same meaning as above, whereas Y denotes an oxygen or sulphur atom or a =N-OH group with an aminoalkyl derivative of the general formula /III/ <IMAGE> /III/ wherein R, R1 and A have the same meaning as stated above and Z means a halogen atom or a H2N-O- group or a salt thereof in the presence of a basic condensing agent. The new compounds of the general formula /I/ possess valuable nicotine-lethality inhibiting, local anaesthetic, analgesic effects, which are, in case of certain compounds, complemented by anti-hypertensive, maximum electroshock and tetracorspasm inhibiting, ulcus inhibiting and motility inhibiting effects, and can be applied to advantage in the therapy.
    公开号:SU927111A3
    申请号:SU802942954
    申请日:1980-07-02
    公开日:1982-05-07
    发明作者:Будаи Золтан；Лаи Ласло；Мезеи Тибор；Петец Луиза；Грассер Каталин；Кошоцки Иболиа；Сирт Енике；Герег Петер
    申请人:Эдьт Дьедьсерведьесети Дьяр(Фирма)；
    IPC主号:
    专利说明:

    () METHOD OF OBTAINING OXYMESTERS OR SALTS
    I
    The invention relates to a process for the preparation of new oxime esters of the general formula
    -R
    (sig) y
    Bj-ch
    Cd
    straight chain
    where a or branched S. -Ce alkylene, 15
    lower alkyl
    R and R,, each or together with the neighboring nitrogen atom form piperazinyl, which can be substituted with ,, alkyl or benzyl.
     Rj, like - hydrogen or
    together form a double bond, R lower alkyl
    or (3-alkenyl |
    P- ,
    or their salts, which have valuable pharmacological properties. A known method for the preparation of oxime 10 zfir of general formula
    --T.
    (SNg) C N-0-A-N
    i P
    Vc
    I rz
    PJI-CM-BI
    where R and R are hydrogen and together mean a valence bond; R ,, and RI, are hydrogen or C — Cc-alkyl or together form an alkylene Cc-C chain, which may also contain an oxygen atom 3 or an —NR group, where R is hydrogen, C C-alkyl or benzyl, Ill — phenyl, which may be substituted by halogen by one or more C C / (- alkoxy groups or nitro groups, A - unbranched or branched, - alkyl of P - 3-10, their salts or Quaternary ammonium pains, which consists in the interaction of the corresponding oxime with haloalkylamine the general formula Hal-AN b, the radical values are indicated above. The process is carried out in inert in the presence of the main condensing agent with the subsequent isolation of the target product in free form or in the form of a quaternary ammonium salt 1. The aim of the invention is to develop a process for the preparation of new oxyamines that have high biological activity, based on the well-known method. biologically active hydroxy esters, or their salts, based on the known reaction described above, which lies in the fact that the compound of the general formula (- with / -ON 2 B4
    where, Riji and p - have the indicated meanings; y is a hydrogen atom or sepa or,
    exposed to a compound of general formula
    x-r
    lit

    RI
    where R, R and L have the indicated meanings,
    Z is halogen or, or a salt thereof in the presence of a basic condensing agent, and the desired product is isolated in free form or in the form of a salt.
    Suppression of nicotine mortality is determined in white mice by the ston method. The results are summarized in
    tab. 2
    table 2
    10.0
    155 16.0
    190 I4 New compounds according to the invention have valuable pharmacological properties, especially inhibiting nicotine mortality, local anesthetic, analgesic, as well as hypertensive (hypotensive), suppressing maximum electric shock (MASH) and inhibiting cardiac spasm, suppressing sound and motility, like This was shown by numerous experiments. The acute toxicity of the compounds of general formula I is measured in white mice, male and female (CFLP rola, weight 18-2 g). The test compound is administered orally and intraperitoneally at a dose of 20 ml / kg. Animals are observed after treatment for. k days. The results of the experiments are shown by the graphical method and are summarized in table. one. . . IT a b l and c a 1
    5927111
    Continued table.
    Pro / relation table.
    权利要求:
    Claims (1)
    [1]
    Local anesthetic effect 1 Studied in Nervus ischiadicus J rats according to the method of Truant and d Amato, and diethylamino-2,6-dimethyl acetanilide (lidocaine) is used as a comparative substance.  The number of animals showing characteristic motor paralis and the duration of this action are recorded.  3 summarizes the relative action attributed to lidocaine (by assigning it a value of 1), and the duration of the action, we observe with the introduction of a 0.25% concentration Table 0.15 9 0. 25 lidoc anesthetizing effect is determined on mice by the method of Koster R Anderson M etal. The results are given in Table.  .  Table The hypotensive effect of the novel compounds according to the invention is tested on anesthetized cats.  Example 7 shows, at doses of 3 and 5 mg / kg, a continuous decrease in blood pressure of 0 mm Ilg.  This compound also possesses noradrenaline-antatonizing (intravenous EDO 2.3 mg / kg) and isoproterenol-antagonizing (intravenous ECO 2.5 mg / kg) properties.  In addition to the blocking (alpha and beta receptors) action, this compound eliminates the occlusive effect of the carotid artery.  The named compound has no effect on orthostatic hypotension.  In awake rats with normal blood pressure, the compound of Example 7 at an oral dose of 100 mg / kg causes a decrease in blood pressure of 13 mm Hg.  The listed experimental results show that compounds of general formula I also have analgesic and antihypertensive properties.  The daily oral dose of the compounds of general formula I is generally 1-100 mg.  However, these values are only informative in nature and the doses to be administered in this case may lie, according to the medical prescription, also below or above the specified interval.  Example 1  Getting 2-n-butyl-1- (2-dimethylaminoethoximino) -cyclohexane.  A solution of 16.9 g (0.1 mol) of 2-n-butyl-cyclohexanone oxime and 200 ml of anhydrous toluene is added to a suspension of 2.4 g (0.1 mol) of sodium hydride in 500 ml of anhydrous toluene.  The mixture is heated under reflux for 2 hours and then mixed with 11.8 g (0.11 mol) of 1-dimethylamino-2-chloro-ethane.  The reaction mixture is heated under reflux for a further 7 hours for 6 hours, then washed with water and extracted with a solution of 15 (0.1 mol) tartaric acid in 100 ml of eody (or from 0.11 mol of diluted aqueous hydrochloric acid).  The aqueous solution with a concentrated solution of ammonium hydroxide is alkalinized to pH 10.  The precipitated oil base is extracted with dichloroethane.  After evaporation of the solids, the residue is fractionated under reduced pressure.  The yield of 18.5 g (76.91 from the theoretical).  The boiling point of the resulting matt yellow oil is 107-108 / 53.32 P The hydrofumarate melts at 68-69. Calculated: C 60.65i H 9.05, N 7.36.  Ciflj os.  Found: C, 60.17; E, N 7.0.  Example 2 Preparation of 2-n 6-Util-1- (2-diethylamino-ethoximino-cyclohexane.  The experiment was carried out as in Example 1, but instead of 1-dimethylamino-2-chloroethane, 1.9 g (0.11 mol) of 1 Diethylamino-2-chloroethane was used.  Yield 9.3 g (72.1 from the theoretical).  The boiling point of the resulting yellowish oil is 114115 ° C / 0, 0 Pa.  The hydrofumarate melts at 73 7.5 ° C.  Calculated,%: C b2.7, H 9.3, N 7.28.  .  Found: C, 62.30; And 9; N7.31.  Example 3  Preparation of 2-n-butyl-1- (3-dimethylaminopropoxyimino) -cyclohexane.  The experiment was carried out as in Example 1, with the difference that instead of 1-dimethyl-amio-2-chlorozane, 13.3 g (0.11 mol) of 1-dimethylamino-3 chloropropane was used.  Yield 17 g (68.5 from the theoretical).  The boiling point of the resulting matt yellow oil is P4-P5s / 40.0 Pa.  The hydrofumarate melts at: Calculated: C 61.59, H 9.25; N 7. 56.   Found: C 61.70, H 9.0, N 7.52.  -Example k.  Preparation of 2-n-butyl-1- (3 Dimethylamino-2-methyl ipropoxyimino) -cyclohexane.  18 The experiment was carried out as in Example 1, with the difference that instead of 1-dimethylamino-2-hl of p-ethane, 16.5 g (0.11 mol) of 1-dimethylamino-3-chloro-2-methyl propane  The output of 18.7 g (69.8% of theoretical).  The melting point of the resulting matt yellow oil is 7 ° C / 2b, 66 Pa.  The hydrofumarate melts at 120121С. Calculated: С b2.7 H 9.3, N 7.28.   Found: C 62.6 H 9.79, N 7.27.  Example 5  Preparation of 2-n-butyl-1 - (3 - (V-benzylpiperazinyl-propoxyimino) -cyclohexane.  A suspension of 2.4 g (0.1 mol) of sodium hydride in 100 ml of anhydrous toluene is mixed drop by drop with a solution of 16.9 g (0.1 mol) of 2-n-butyl-cyclohexanone oxime in 100 ml of anhydrous toluene.  The mixture was heated under reflux for 2 hours and then a solution of 27.8 g (0.11 mol) of 1-DM-benzyl-piperazinyl / -3-chloro-propane and 50 ml of anhydrous toluene was added.  The reaction mixture is heated to boiling for 12 hours, then cooled and extracted with a solution of 35 g of tartaric acid in 150 ml of water.  The aqueous phase is made basic with ammonium hydroxide to pH 10 and extracted with dichloroethane.  After removal of the solvent, the remaining base is transferred to the corresponding salt.  The yield of 27.5 g (71.6 from the theoretical).  The melting point of dihydrofuramate is 200-202 ° C.  Calculated: C b2, 72, H 6.90, N 6.86.  СггццМ% Od.  Found: C 62.70, And 6.68, N 6.82.  Example 6  Preparation of 2-n-butyl-1 - (3- (4-methyl piperazinyl) -propoxyimino / -cyclohexane.  The test was carried out as in Example 5, with the difference that instead of 1- (N-6eHzyl-piperazinyl) -3-chloro-propane, 19.5 g (0.11 mol) of 1- (M-methyl-piperazinyl) - 3-chloro-propane.  The yield of 28.0 g (92.4 from the theoretical).  The melting point of dihydrofumarate is 199-202 °.  Calculated: C 57.64; H 8.00, N 7.75.  C, en ,, NjO.  FoundD: C, H 8.10, N 7.7.  Example 7  Preparation of 2-butylidene-1- (3-methylpiperazinyl-propoxyimino / -cyclohexane; From 3.9 g (0.1 mol) of sodium hydride, 16.8 g (0.1 mol) of 2-butylidene cyclohexanone oxime are obtained in this case, the sodium salt, which is mixed with 19.5 g (0.11 mmol) of 1- (N-methylpiperazinyl) -3-chloro-propane. The reaction mixture is treated according to the method described in example 1.  Yield 25.2 g (83.4 from the theoretical).  The melting point of the resulting dihydrofumarate C.  Calculated: C 57.89; H 7.66, N 7.78.  SubImN Og Found D: C 57.65, H 7.52; N 7.70.  The melting point of dihydrotatrate is 72-73 °.  Calculated: C 51.39; H 7 ,, N 6.92.  Cge HiisNsas Found: C, 51.17; H 7.39, N 6.87.  The melting point of dihydrochloride is 184-186 ° C.  Calculated: C 5b, 83, H 9.27 CI 18.6, N 11.05.  C HspCljNtO Found;%: C 56.68; H 9.11, cr 18.60; N and, 00.  The melting point of diiodide 1,1, -trimethyl- - (2 -butylidene-1-cyclohexylidene) -oxy-propyl / -pip rasinyl is 269-27 ° C.  Calculated: С 0.62, H 6.6, N 7.1G, 2.92.  .  .   “.  Found,%: C 41, OG, H 6.82, N 7.10,: i 3.10.  Example 8  Preparation of 2-butylidene-3-C-benzyl-piperazinyl) -propoxy-imino / cyclohexane.  The experiment was carried out as in Example 5, with the difference that 2.4 g (0.1 mol) of sodium hydride, 16.8 g (0.1 mol) of 2-butylidene-cyclohexanone-oxime were used as the starting material. and 27.8 g (0.11 mol) of 1- / benzyl-piperazinyl / -3-chloro-propane: Yield 26.7 g (67.9 from the theoretical).  1110 Melting point of dihydrofumarate 187-189.  Calculated,%: C 62.42) H, 7.36 N, 6.82.   Found: C 62.30, H 7.50, N6.78.  PRI me R E.  Preparation of 2-pentylidene-1- [3 (4-methyl-piperazinyl) -propoxyimino] -cyclohexane.  The experiment was carried out as in Example 5 with the difference that 2.4 g of fO, 1 mol of sodium hydride, 18.2 g of Co, 1 were used as the starting material.  mol) 2-pentylidene-cyclohexanone-oxime-and 19.5 g (0.11 mol) of 1 - (N-methyl-piperazinyl) -3-chloro-propane.  The yield of 25.8 g (79.5% of theoretical).  The melting point of dihydrofumarate is 193-195 ° C.  Calculated,%: C 58.49; H 7.82, N 7.53.  CarHf, iNi03 Found,%: C 58.30; H 7.68, N 7. 61.  Example 10  Preparation of 2-pentylidene-1- [3- (4-benzyl pipa razinyl] propoxyimino] -cyclohexane.  The experiment was carried out as in Example S, with the difference that 18.2 g (0.1 mol) of 2-pentylidene-cyclohexanone-oxime was used as the starting material.  The output of 25.3 g (63.6% of theoretical).  The melting point of dihydrofumarate is 200-202C.  Calculated,%: C 62.93, H 7.52, N 6.67.  CjiHi TN Og Found: C62.79, And 7.48, N 6.70.  Example 11  Preparation of 2-propylidene-1- [3- (4-methyl-piperazinyl) -propoxyimino] -cyclohexane.  The experiment was carried out as in Example 5, with the difference that 2.4 g (0.1 mol) of sodium hydride, 15.4 g (0.1 mol) of 2-propylidene-cyclohexanone oxime were used as the starting material. and 19.5 g (0.11 mol) of 1- / N-methyl-piperazinyl / -3 chloropropane.  Yield 24.2 g (82.5 from the theoretical).  The melting point of dihydrofumarate is 188-189 ° C.  Calculated,%: C 57.14, H 7.48, 7.95.  11 CU-HI N OJ.  Found D: C 56.85, H 7.25, N 7.80.  Example 12  Preparation of 2-6Ulidene-1- [3- (methyl-piperazinyl) -propoxyimino] -cycloheptane.  The experiment was carried out as in Example 5, with the difference that the sodium salt was obtained from 2, g (0.1 mol) of sodium hydride and 18.2 g (0.1 mol) of 2-butylidene-cycloheptanone oxime in toluene , and the sodium salt obtained is reacted with 19.5 g (0.11 mol of 1- / H-melyl-piperazinyl / -3 chlor-pro-Pan.  The yield of the target product is 29.5 (89.1% of the theoretical).  The melting point of dihydrofumarate is 213-216 ° C.  C 58.57; H 7.82; Calculated N 7.59.  , .  C 58.25; H 7, Found, N 7. 38  Example 13  Preparation of 2-butyliden-1- / 3 dimethylamino-2-methyl-propoxy-imino / -cyclohexane.  The experiment was carried out as in Example 1, with the difference that 16.8 g (0.1 mol) of 2-6 utilenidene-cyclohexanone oxime and 16.5 g (0.11 mol) of 1-dimethylamino -Z-chloro-2-methylpropane The yield of the target product is 22.3 g (90.6% of the theoretical).  The melting point of hydrofumarate is 13 -1364.  Calculated: C 62.68, H 8.95 N. p and 1-1 g, NiD Found;% C b 2.87, H 8.75, N7.32.  Example 14  Preparation of 2-allyl-3 / -methyl-piperazinyl / -prop sy-imino / -cyclohexane.  The experiment was carried out as in Example 5, with the difference that the sodium salt was obtained from 2, g (0.1 mol) of sodium hydride and 15.3 g (0.1 mol) of 2-al lyl cyclohexanone oxime in toluene, and the resulting sodium salt is mixed with 19.5 g (0.11 mol) of 1- / N-Methylpiperazinyl / -3 chloropropane.  The yield of the target product is 25.2 g (86.1% of the theoretical).  The melting point of dihydrofumarate is 192-195 C.  Calculated,%: C 57.2+; H 7.30, N 8.01.  112 CjsHigNsOs.  Found,%: C 57.00) H 7, + 5, N 8.02.  Example 15  Preparation of 2-hexylidene-1- / 3 C -methyl-piperazinyl) -propoxy-imino / cyclohexa.  The test was carried out as in Example 5, with the difference that 2, C g (0.1 mol) sodium hydride, 19.5 g (0.1 mol) 2-hexylidene-cyclohexanone-oxime were used as the starting material. and 19.5 g (0.11 mol) of 1- / N-methyl-piperazinyl / -3 chloropropane.  The yield of 28.8 g (86.1% of theoretical).  Calculated,%: C 59.2; H 7.99; N 7.0.  SgvNtsbM Oh.  Found,%: C 59,011 H 8, N 7.36.  Example 16  Preparation of 2-octylidene-1- [3-C-methyl-piperazinyl] -propoxy-imino / cyclohexane.  The experiment was carried out as in Example 5, with the difference that 2.4 g (0.1 mol) of sodium hydride and 22.3 g (0.1 mol) of 2 octylidene-cyclohexanone-oxime in toluene and sodium hydroxide were mixed. salt is mixed with 19.5 g (0.11 mol) of T-xM-methyl-piperazinyl / -3-chloro-propane.  The output of 38.5 g (9% of theoretical).  The melting point of dihydrofumarate is 200-203 °.  Calculated,%: G 60.8, H 8.29, N 7.05.  CboHi ,.  Found,%: C 60.62, H 8.36, N 27.10.  Example 17 Preparation of 2-n-butyl / 2-diethylaminoethoxyimino / -cyclohexane.  15 g (0.1 mol) of 2-n-butyl-cyclohexane and 22.61 g (0.11 mol) of diethylaminoethoxyamine dihydrochloride are heated for 1 h to boil in a mixture of 150 ml of anhydrous ethanol and 7 ml of anhydrous pyridine and then evaporated under reduced pressure.  The residue is basified to pH 10 with a 40% aqueous solution of sodium hydroxide, the base formed is extracted with dichloroethane, and the extract is dried.  The yield of 21.23 g (79.3% of theoretical).  Boiling point 1 Ti-l, 0 Pa. Matte yellow oil.  Hydrofumarate melts at C.  13 Calculated: C 62, k7, H 9 ,, N 7.28.  C lbs Os Found: C 62.30, H 9 ,, N 7.31.  Example 18  Obtaining 2-n-butyl-1- / 2-dimethyl-aminoethoxyimino / -cyclohexane.  The experiment was carried out as in Example 17 with the difference that 15, g (0.1 mol) of 2-n-butyl-cyclohexane 17.7 g (0.11 mol) of dimethylaminoethoxyamine dihydrochloride were used as the original substance.  The yield of the target product is 20, g (8k, L% of the theoretical).  The hydrofumarate melts at 68-b9. Example 19- Preparation of 2-n-butyl-1- (3-dimethylamino-2-methyl-propoxy-imino / -cyclohexane).  The experiment was carried out as in example 17 with the difference that 15, g (0.1 mol) of 2-n-butyl-cyclohexane and 30.76 g (0.15 mol) of dihydrochloro -1- dimethylamino-2-methylpropoxiams on.  Yield 20.60 g (76.8% of theoretical).  .  The hydrofumarate melts at 120121 ° C.  Example 20  Obtaining 2-n-butyl-1- / 3-dimethylaminopropoxy-imino / -cyclohexane.  The experiment was carried out as in Example 17 with the difference that 15, g (0.1 mol) 2-n-butyl-cyclohexanone and 21.0 g (0.11 mol) of dimethylaminopropoxyamine-dihydrochloride were used as the raw material. The output of 20.0 g (78.8% of theoretical).  The hydrofuramate melts at PI.  me er 21.  Preparation of 2-n-butyl-1- [3-C-benzyl-piperazinyl-propoxy-imino] -cyclohexane.  The experiment was carried out as in Example 17 with the difference that 15, g (0.1 mol) of 2-n-butyl-cyclohexane and 37.7 g (0.11 mol) of T-Hamino-oxypropyl / - -benzyl piperazine trihydrochloride.  The yield of 28.9 g (75.6% of theoretical).  The dihydrofumarate melts at 201-202 ° C.  Example 22  Preparation of 2-n-butyl-1- (3- (V-methyl-piperazinyl) -propoxy-imino / -cyclohexane.   carried out as in example 17 with the difference that S, 0.1 g of 2-n-butyl-cyclohexane and 31.1 g (0.11 mol) of trihydrochloride 1- (amio nooxypropyl) - - methyl piperazine.  The yield of 28.9 g (95, from theoretical).  The dihydrofumarate melts at 211213C.  Example 23  Preparation of 2 -butylidene-1- [z- (-benzyl-piperazinyl) -propoxy-imino] -cyclohexane.  The experiment was carried out as in Example 17, with the difference that 15.2 g (0.1 mol) of 2-butylidene-cyclohexanone and 37.7 g (0.11 mol) of 1- / aminooxypropyl trihydrochloride were used as the raw material. / - -benzyl-piperazine.  The output of 30.62 g (77.9% of theoretical).  The dihydrofumarate melts at 187189 ° C.  Example 2k, Preparation of 2-pentylidene-1- (3-C-benzyl-piperazinyl) -propoxy-imino / -cyclohexane.  The experiment was carried out as in Example 17, with the difference that 16.6 g (0.1 mol) of 2-pentylidene-cyclohexane and 37.7 g (0.11 mol) of trihydrochloride 1- (amm nooxypropyl) - -benzyl-piperazine, Yield 27, OT g (70% of theoretical).  The dihydrofumarate melts at 200202 ° C.  Example 25  Preparation of 2-ALIL-1- / 3 - (- methyl piperazinyl) -propoxy-imino / -cyclohexane.  .  The experiment was carried out as in Example 1, with the difference that 13.8 g (0.1 mol) of 2-allyl-cyclohexanone and 31.1 g (0.11 mol) of 1- (aminooxypropyl) trihydrochloride were used as raw materials. - -methyl-piperazine.  The yield of 22.68 g (77.5% of theoretical).  Dihydrofumarate melts at 19 +196 0.  Example 26  Preparation of 2-butylidene-1- / 3 (k -methyl-piperazinyl) -propoxyimino / -cyclohexane -.  The experiment was carried out as in example 17, with the difference that 15.2 g (0.1 mol) of 2-butylidene-cyclohexane and 31.1 g (0.11 mol) of 1 - (aminoxypropyl ) - -methyl-piperazine.  The yield of 27.7 g (91; 7% of theoretical).  The dihydrofumarate melts at 197.  15 Example 27.  Preparation of 2-butylidene-1- [3-Ci -methyl-piperazinyl- (ipropoxy-imino] -cycloga. The experiment was carried out as in example 17i with the difference that 16.6 g (0.1 mol) of 2-butyl 1idene-cycloheptanone and 31 were used as raw materials. 1 g (0.11 mol) of 1- (amine hydroxypropyl) -4-methyl piperazine trihydrochloride.  Yield 28 g (Qk, S% of the theoretical dihydrofumarate melts at 215-217 ° C).   Example 28  Preparation of 2-pen tilidene-1- / 3 (-methyl-piperazinyl-propoxy-imino / -cyclohexane. The experiment was carried out as in Example 17, with the difference that as a raw material.  16.6 g (0.1 mol) of 2-pentylidene-cyclohexanone and 31.1 g (0.11 mol) of 1- (aminooxypropyl) -methyl-piperazine trihydrochloride are used.  Yield 28, g (87.5% of theoretical), Dihydrofumarate melts at IS 1. 96 ° C.  Example 29  Preparation of 2-pro pilidin-1- / 3-methyl-piperazinyl) -propoxy-imino / -cyclohexane.  The experiment was carried out as in example 17, with the difference that 13.8 g (0.1 mol) of 2-propylidene-cyclohexanone and 31.1 g (0.11 mol) of 1- (aminooxypropyl trihydrochloride trihydrochloride) were used as the raw material. ) - -methyl-piperazine.  Yield 22.99 g (78, from theoretical).  The dihydrofumarate melts at 189,190 ° C.  Example 30  Preparation of 2-6Ulidene-1- / 3 C -methyl-piperazinyl-propoxy-imino / -cyclohexane.  The experiment was carried out as in example 17, with the difference that 1b, 8 g (0.1 mol) of 2-butylidene-cyclohexation and 31, T g (0.11 mol) of 1- (aminooxypropyl ) - -methyl-piperazine.  Yield 21 g (70.3% of theoretical).  Example 31-Preparation of 2-butylidene-1- / 3 (-methyl-piperazinyl-propoxy-imino / -cyclohexane.  From 6.9 g (0.3 g-atom) of metallic sodium and 50 ml of anhydrous methanol, a solution of sodium methoxide is obtained, which is added to.  a solution of 16.8 g (0.1 mol) of 2-butylidene-cyclohexanone-oxime in 150 ml of anhydrous (MS) methanol.  Psch; l (. ; Drugs D) Hydrogen release was added sparingly with 27.5 g (0.11 mol) of 1- / K-methyl-piperazinyl / -3-chloro-propane dihydrochloride.  The reaction mixture is heated to boiling for several hours, then separated from the salt and evaporated.  The yield of 29.5 g (97.6, from theoretical).  The dihydrofumarate melts at 1961984.  Example 32  Getting 2-butylidene-1- / 3 (-methyl-piperazinyl) -propoxyimino / -cyclohexane.  To a suspension of 2, C g (0.1 mol) of sodium hydride in 50 ml of anhydrous toluene and 30 ml of anhydrous dimethylformamide, a solution of 16.8 g (0.1 mol) of 2-butylidene-cyclohexanone-oxime in 150 ml of anhydrous toluene is added.  Withstand the mixture. at 100 ° C for 2 hours, after which 19.5 g (0.11 mol) of 1- (K-methyl-piperazinyl) -3-chloro-propane is added.  The reaction mixture is kept at 100 ° C for several hours, after which it is washed twice with 50 ml of water and concentrated under reduced pressure.  Yield 26.2 g (86.7 from the theoretical).  Dihydrofumarate melts at 19 ° 197 ° C.  PRI me R 33.  Getting 2-allyl-1- / 3 (-methyl-piperazinyl) -propoxyimino / -cyclohexane.  2.4 g (0.1 mol) of sodium hydride, 15.3 g (0.1 mol) of 2-allyl-cyclohexanone-oxime and 19.5 g (0.11 mol) of 1- / H-methyl-piperazinyl / -3 Chloropropane was converted as in Example 32, with the difference that 30 ml of anhydrous dimethylacetamide was used instead of dimethylformamide.  Yield 26.2 g (88, t from the theoretical).  Melting point of dihydrofumarate 19 -19b C.  Example H.  Preparation of 2-butylidene-1- [3-dimethylamino-2-methyl-propoxy-imino] -cyclohexane.  The experiment was carried out analogously to example 17, with the difference that 15.2 g (0.1 mol) of 2-butylidene-cyclohexanone and 22.6 g (0.11 mol) of 1-dimethylamino-2- dihydrochloride dihydrochloride were used as the raw material. methyl-3-aminooxypropane.  Yield 22.9 g (93 ° of theoretical).  Melting point hydrofumartl.  179271 Example 35- Preparation of tablets of the following composition: Active substance 2-n-butyl-1- / 2-dime-5 thyl-amino-ethoxy-imino / -cyclohexane hydromethyl fumarate, mg Corn starch, ml Polyvinylpyrrolidone, ml magnesium stearate, ml Under total weight 300 mg, active substance 25 mg.  A mixture of the active substance and corn starch with a 10-15% aqueous solution of polyvinylpyrrolidone is granulated with wet and then dried at 40-5 ° C.  The dry granules are sieved again, mixed with talcum powder and sodium stearate and transferred to tablets.  Example 36  Obtaining pills of the following composition, mg: Active substance 2-butylidene-G / C-C-methyl piperazinyl) -propoxy-imino / -cyclohexane dihydrofumarate 25.0 Cornstarch, mg2 5.0 Gelatin8.0 Talc 18.0 Magnesium stearate, 0 With a total weight of 300.0 mg, the active substance content is 25.0 mg.  The mixture of active substance and corn starch is moistened with a 10% aqueous solution of gelatin, sieved, granulated and dried.  The dried granulate is re-sieved, homogenized with talc and magnesium stearate and pressed into a dragee.  Example 37  Obtaining pills of the following composition, mg: Active substance 2-octylidene-1- / 3 - (C-methyl-piperazinyl) -propoxy-imino / -cyclohexane dihydrofumarate 50.0 Milk sugar 97.0 Polyvinylpyrrolidon2.0 Magnesium stearate 1.0 11 The description of the izvesticheskogo pische ohm suli zyra drip of ruled water of the Southeastern Sea.  total 18 With a total weight of 150.0 mg of active substance 50.0 mg.  The preparation was carried out according to the method described in Example 37.  The grain weight is 150 ml.  These grains are naturally covered with a layer of sugar and talcum powder.  Gotodrazhe stained with non-toxic evy dye and polished Vos.  Example 38  Preparation of the following composition, mg: Active substance of the general formula 25.0 Corn starch 2,65 Aerosil 6,0 Magnesium stearate C, O With a total weight of 300.0 ml containing the active substance 25.0 mg These components are homogenized and filled into gelatinous souls of suitable sizes.  Example 39  Preparation of capsules of the following composition, mg: Active substance of general formula I50.0 Lactose90.0 Aerosil6.0 Magnesium stearate 4.0 With a total weight of 150.0 mg containing an active substance 50.0 mg.  These components are homogenized and filled into gelatinous caps of suitable sizes.  Example 0  According to known methods of pharmaceutical industry, solutions for injection are obtained.  Cages contain 25.0 g of the active branch of the general formula 1, dissolved 5 ml of double-distilled y.  Claim 1.  The method of producing oxymethyls of the formula (CHg) C NO-A-Nr V Y 7 O 3-s - straight chain or branched C-Cb-alkylene; 1992711 R and R. each is alkyl or together with the adjacent nitrogen atom form piperazinyl, which may be substituted with C -C alkyl or benzyl; RJ, and R ,,, each - hydrogen or o together form a double bond, the lowest. alkyl or C2-C40-alkenyl, ti or their salts, consisting in that the compound of the general formula.  (2) „f Y V. C / Cs-ck g 1 where the base where or go to chenn Svol.  20 and p have the indicated values, y represents hydrogen or sulfur or H-III, reacts with the compound of the general formula g-A- and R, RI and A have the indicated values, Z is a halogen or -O-III with its salt in the presence of a base-condensing agent and the compound is recovered, either in one form or as a salt.  Sources of information that are considered in the examination.  Patent of the USSR №, С 07 С 131/02, publ.  15. eleven. 78
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    同族专利:
    公开号 | 公开日
    GR68751B|1982-02-16|
    PL122750B1|1982-08-31|
    DK150197C|1987-11-02|
    DE3025238A1|1981-03-26|
    CS217979B2|1983-02-25|
    SE8004868L|1981-01-04|
    DE3025238C2|1989-02-02|
    NO801993L|1981-01-05|
    CH650249A5|1985-07-15|
    DD151933A5|1981-11-11|
    FR2460294B1|1983-03-11|
    ES8105704A1|1981-06-01|
    AT372677B|1983-11-10|
    DK286480A|1981-01-04|
    AU6003580A|1981-01-15|
    NO148451C|1983-10-12|
    JPH0135822B2|1989-07-27|
    IL60359D0|1980-09-16|
    CA1146170A|1983-05-10|
    GB2055808B|1983-02-16|
    NO148451B|1983-07-04|
    FI70579B|1986-06-06|
    YU35984A|1984-08-31|
    FI70579C|1986-09-24|
    US4395413A|1983-07-26|
    BE884083A|1980-12-30|
    ES492949A0|1981-06-01|
    SE446979B|1986-10-20|
    ATA344880A|1983-03-15|
    PL225405A1|1981-06-05|
    YU42672B|1988-10-31|
    GB2055808A|1981-03-11|
    NL8003846A|1981-01-06|
    HU180739B|1983-04-29|
    IT8023208D0|1980-07-03|
    YU174280A|1984-08-31|
    DK150197B|1987-01-05|
    YU43344B|1989-06-30|
    NL190371B|1993-09-01|
    FI802111A|1981-01-04|
    AU530184B2|1983-07-07|
    JPS5610161A|1981-02-02|
    NL190371C|1994-02-01|
    IL60359A|1985-04-30|
    IT1148881B|1986-12-03|
    FR2460294A1|1981-01-23|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US1733462A|1926-09-23|1929-10-29|Winthrop Chem Co Inc|New basic oxime ethers of cyclic compounds|
    US4083978A|1976-01-27|1978-04-11|Egyt Gyogyszervegyeszeti Gyar|Oxime ethers|
    GB1493222A|1976-01-27|1977-11-30|Egyt Gyogyszervegyeszeti Gyar|Cycloalkanone oxime ethers and process for the preparation thereof|HU189227B|1983-02-08|1986-06-30|Egyt Gyogyszervegyeszeti Gyar,Hu|Process for preparing basic oxime-ethers|
    HU188250B|1983-02-08|1986-03-28|Egyt Gyogyszervegyeszeti Gyar,Hu|Process for producing of basical oxim-ethers|
    US4735943A|1984-06-29|1988-04-05|Sanwa Kagaku Kenkyusho Co., Ltd.|Eburnamonine oxime derivatives, salts thereof, and pharmaceutical agents containing the same|
    HU197205B|1984-07-10|1989-03-28|Egyt Gyogyszervegyeszeti Gyar|Process for production of medical compositions against angine|
    FR2593501B1|1986-01-29|1988-05-06|Panmedica Sa|NOVEL BIS-5,7 DIHYDRO-6,7DIBENZOCYCLOHEPTENE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS|
    HU202195B|1987-12-31|1991-02-28|Egyt Gyogyszervegyeszeti Gyar|Process for producing new substituted styrene derivatives and medical compositions comprising such compounds|
    HUT67314A|1993-04-09|1995-03-28|Egyt Gyogyszervegyeszeti Gyar|Process for prepg. new trisubstituted cykloalkane deriv.s and pharmaceutical compn.s contg. them|
    FR2728571B1|1994-12-22|1997-01-31|Adir|NOVEL ETHERS OF TRICYCLIC OXIMES, PROCESSES FOR THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
    DE19722848A1|1997-05-23|1998-11-26|Schering Ag|Leukotriene B¶4¶ derivatives, especially Oximo LTB¶4¶ antagonists|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HU79EE2675A|HU180739B|1979-07-03|1979-07-03|Process for producing basic oxime-ethers|
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